Generation of mutant proteins via adversarial attacks on the AlphaFold2 model

Announcement of a new publication in the magazine. Proteins are essential macromolecules that perform functions according to their conformational dynamics. The study of conformational changes induced by protein mutations is a standard approach used to understand the underlying mechanisms mutation-related physiological and pathological processes.

To increase the efficiency and reduce the cost of biological experiments, this paper presents a method to generate mutant proteins through adversarial attacks on the AlphaFold2 (AF2) model. The change in structure of opposing protein sequences predicted by AF2 compared to the structure of the wild-type protein was examined. CASP14 experiments showed that changing just three residues by replacement, deletion, or insertion led to a difference of 46.61 points in AF2 predictions, according to the local distance difference test (lDDT).

The method was applied to the transmembrane lipid transporter SPNS2 to identify key residues and suggest potential alternative conformations, thereby improving the experimental phase in structure determination and mechanistic studies.